This application addresses broad challenge Area (05): Comparative Effectiveness Research (CER) and specific Challenge Topic, 05-DA-102*: Treatment of Substance Abuse and Related Health Consequences Using Web-Based Technologies. Youth are frequently at the center of the HIV epidemic, and HIV has been referred to as a "youth-driven disease" worldwide. In the U.S., 40% of all new HIV infections occur in persons under age 25 years, and HIV is the 6th leading cause of death among adolescents. Youth who use drugs are at particularly high risk for HIV, as well as other infectious diseases with similar transmission dynamics, such as hepatitis and Sexually Transmitted Infections (STIs), relative to their non-drug using peers. Several HIV prevention interventions have been shown to be effective with adolescents, but they are infrequently provided to youth, even in formal systems of care such as adolescent substance abuse treatment programs. Additionally, virtually no adolescent substance abuse treatment programs offer evidence-based interventions targeting STIs or hepatitis. Evidence-based prevention interventions are expensive to implement and strain available resources, given the limited staffing and high caseloads at the average substance abuse treatment program. Even if evidence-based HIV prevention interventions are initiated by staff in community treatment programs, it may be difficult to ensure their fidelity. Thus, the limited compatibility of research-based interventions with treatment agency realities may present numerous operational barriers to the transfer of evidence-based practice in community-based settings. We previously developed an interactive, customizable, web-based program focused on the prevention of HIV, STIs and hepatitis for youth that incorporates effective components of both prevention science and educational technologies that promote mastery of key skills and information. This tool allows a complex intervention to be delivered with high fidelity and at low cost, without increasing demands on staff time or training needs. We demonstrated that this web-based tool, when provided as an adjunct to an educator- delivered HIV and infectious disease prevention intervention, enhanced desired outcomes (e.g., increased accurate HIV/disease prevention knowledge, increased intentions to reduce risk behavior) relative to the educator-delivered prevention intervention when provided alone. However, given that so few adolescent substance abuse treatment programs have the resources to offer traditionally-delivered, evidence-based HIV, hepatitis, and STI prevention interventions, understanding the independent effectiveness of this self-directed, web-delivered intervention (as a stand-alone intervention) is a clinically important question. In the presently proposed trial, we will examine the comparative effectiveness and cost-effectiveness of the web-based HIV, hepatitis and STI prevention intervention when offered to youth in outpatient, community- based substance abuse treatment when directly compared to a traditional (educator-delivered) HIV and infectious disease prevention intervention. We will assess the comparative effectiveness of these interventions by primarily examining changes from pre- to post-intervention in accurate HIV/disease prevention knowledge, intentions to engage in safer sex, and HIV risk behavior. Additionally, we will examine the extent to which the interventions impact relevant skills acquisition (e.g., communication skills, negotiation skills and condom use skills), attitudes toward safer sex, and self-reported substance use. We will also examine the acceptability of each intervention (e.g., by asking youth to rate how useful, interesting, etc. each intervention was). We also plan to evaluate youth at both 1 and 3 month post-intervention to examine the durability of effects (including any differential durability of effects across intervention conditions). We will also perform an economic analysis of the web-based program in community-based, adolescent substance abuse treatment programs. We will estimate the incremental cost-effectiveness ratio of this web- delivered intervention relative to the educator-delivered intervention from a societal perspective (presented as costs per HIV infections prevented, estimated from changes in HIV risk behavior). We will also estimate cost- effectiveness from the substance abuse treatment program's perspective and payer's perspective to better understand the factors impacting the adoption of this intervention at the local level. Because of the considerable cost constraints within treatment programs, demonstration of effectiveness is not sufficient for implementation of evidence-based practice. Rather, demonstration of cost-effectiveness is necessary. A technology-based approach to HIV prevention creates new opportunities and outlets for intervention efforts that are not tied to traditional strategies. This web-based tool, and similar technology-based interventions, if found effective and cost-effective, could substantially advance the substance abuse treatment system by markedly improving the availability and quality of HIV prevention interventions delivered to individuals in such treatment settings. Importantly, this web-based intervention can transcend geographic boundaries, thus enabling its use, in future applications, in a wide variety of settings where HIV prevention interventions for youth are typically limited (e.g., schools, health care providers'offices, online social networks). This web-based system can also be expanded to address other issues, such as evidence-based skills training (e.g., self-control training), substance abuse psychosocial treatment/relapse prevention and mental health issues. Thus, our proposed project has the potential to greatly increase the pace and achievement of research examining the effectiveness of technology-based interventions targeting behavioral health. Public Health Relevance Statement The computerized intervention we propose to evaluate in this project, if found effective and cost-effective, could substantially advance the adolescent substance abuse treatment system by markedly improving the availability and quality of HIV (and infectious disease) prevention interventions delivered to youth in such settings. Further, this intervention is web-based, thus enabling its use in a wide variety of settings where HIV prevention interventions for youth are typically limited (e.g., schools, health care providers'offices, online social networks). The proposed project may generate clinically and economically meaningful data regarding the use of technology in promoting new models of delivery of science-based HIV prevention for adolescents, with the potential to have a substantive impact in changing the trajectory of the HIV epidemic among youth.